Prostaglandin E(2) is a selective inducer of interleukin-12 p40 (IL-12p40) production and an inhibitor of bioactive IL-12p70 heterodimer.

Interleukin-12 p70 (IL-12p70) heterodimer, composed of p35 and p40 subunits, is a major Th1-driving cytokine, promoting cell-mediated immunity. In contrast, IL-12p40 homodimer, secreted by APC in the absence of p35 expression, and free p40 monomer do not mediate IL-12 activity but act as IL-12 antagonists. Here it is reported that prostaglandin E(2) (PGE(2)), an inflammatory mediator with a previously known Th2-driving function, dose-dependently enhances the IL-12p40 mRNA expression and the secretion of IL-12p40 protein in human tumor necrosis factor-alpha (TNFalpha)-stimulated immature dendritic cells (DCs). This effect is selective and is not accompanied by the induction of IL-12p35 expression or by secretion of IL-12p70 heterodimer. Inability of TNFalpha/PGE(2) to induce IL-12p70 was not compensated by interferon gamma (IFNgamma), which strongly enhanced the lipopolysaccharide (LPS)-induced IL-12p70 production. In addition to the selective induction of IL-12p40 in TNFalpha-stimulated DCs, PGE(2) inhibited the production of IL-12p70 and IL-12p40 in DCs stimulated with LPS or CD40 ligand. These data suggest an additional level of the Th2-promoting activity of PGE(2), via selective induction of IL-12p40. Selective induction of IL-12p40 and suppression of bioactive IL-12p70 may have negative impact on anticancer vaccination with PGE(2)-matured DCs. (Blood. 2001;97:3466-3469)

IL-4 is a mediator of IL-12p70 induction by human Th2 cells: reversal of polarized Th2 phenotype by dendritic cells.

IL-12 is a key inducer of Th1-associated inflammatory responses, protective against intracellular infections and cancer, but also involved in autoimmune tissue destruction. We report that human Th2 cells interacting with monocyte-derived dendritic cells (DC) effectively induce bioactive IL-12p70 and revert to Th0/Th1 phenotype. In contrast, the interaction with B cells preserves polarized Th2 phenotype. The induction of IL-12p70 in Th2 cell-DC cocultures is prevented by IL-4-neutralizing mAb, indicating that IL-4 acts as a Th2 cell-specific cofactor of IL-12p70 induction. Like IFN-gamma, IL-4 strongly enhances the production of bioactive IL-12p70 heterodimer in CD40 ligand-stimulated DC and macrophages and synergizes with IFN-gamma at low concentrations of both cytokines. However, in contrast to IFN-gamma, IL-4 inhibits the CD40 ligand-induced production of inactive IL-12p40 and the production of either form of IL-12 induced by LPS, which may explain the view of IL-4 as an IL-12 inhibitor. The presently described ability of IL-4 to act as a cofactor of Th cell-mediated IL-12p70 induction may allow Th2 cells to support cell-mediated immunity in chronic inflammatory states, including cancer, autoimmunity, and atopic dermatitis.

Development of Th1-inducing capacity in myeloid dendritic cells requires environmental instruction.

Dendritic cells (DC) are key initiators of primary immune responses. Myeloid DC can secrete IL-12, a potent Th1-driving factor, and are often viewed as Th1-promoting APC. Here we show that neither a Th1- nor a Th2-inducing function is an intrinsic attribute of human myeloid DC, but both depend on environmental instruction. Uncommitted immature DC require exposure to IFN-gamma, at the moment of induction of their maturation or shortly thereafter, to develop the capacity to produce high levels of IL-12p70 upon subsequent contact with naive Th cells. This effect is specific for IFN-gamma and is not shared by other IL-12-inducing factors. Type 1-polarized effector DC, matured in the presence of IFN-gamma, induce Th1 responses, in contrast to type 2-polarized DC matured in the presence of PGE2 that induce Th2 responses. Type 1-polarized effector DC are resistant to further modulation, which may facilitate their potential use in immunotherapy.

Corticosteroids inhibit the production of inflammatory mediators in immature monocyte-derived DC and induce the development of tolerogenic DC3.

Corticosteroids (CS) are potent immunosuppressive agents that are known to affect T cell-mediated inflammation by the inhibition of proliferation and cytokine production, as well as the immunostimulatory function of monocytes and macrophages. Not much is known of the effect of corticosteroids on dendritic cells (DC), the professional T cell stimulatory antigen-presenting cells. We report that the endogenous CS hydrocortisone and the synthetic CS clobetasol-17-propionate strongly inhibited the production of the inflammatory mediators interleukin (IL)-12 p70, tumor necrosis factor alpha (TNF-alpha), and IL-6 by lipopolysaccharide (LPS)-stimulated monocyte-derived immature DC (iDC) in vitro. In contrast, the stimulatory capacity, antigen uptake, and the expression of costimulatory molecules were not affected. In accordance with the decreased production of IL-12 p70, CS-treated iDC induced less production of the inflammatory Th1 cytokine interferon-y and enhanced levels of the Th2 cytokines IL-10 and IL-5 in staphylococcal enterotoxin B-stimulated CD4+ Th cells. Furthermore, CS inhibited the maturation of iDC as assessed by the lack of expression of CD83 as well as by the prevention of the loss of antigen uptake capacities. These type 3 DC (DC3) matured in the presence of CS produce less IL-12 p70 and have a decreased T cell stimulatory capacity. Moreover, uncommitted T cells that encounter the CS-induced DC3 develop into Th2-biased cells, which may additionally decrease the Th1-mediated tissue damage but, on the other hand, Th2 cytokines may promote undesirable elevation of IgE and eosinophilia. These findings indicate that suppression of T cell-mediated inflammation by CS not only relies on direct effects on T cells, but also on various effects on DC, their professional antigen-presenting cells.

Glucocorticoids inhibit bioactive IL-12p70 production by in vitro-generated human dendritic cells without affecting their T cell stimulatory potential.

Glucocorticoids (GC) are known to affect the immune response at several stages. However, little is known about how GC influence the initiation of the specific immune response at the level of dendritic cells (DC), the highly professional APC for T cells. Therefore, we studied whether GC modulate the cytokine production and T cell stimulatory function of DC. In LPS-stimulated DC, GC strongly reduced the secretion of the Thl-skewing factor IL-12p70 and, to a lesser extent, the production of the proinflammatory cytokines IL-6 and TNF-alpha. Regarding the T cell stimulatory function of DC, GC did not influence the cell surface expression of HLA-DR or the costimulatory molecules CD40 and CD80 and did not influence the ability of DC to take up Ag. Consequently, GC pretreatment of DC indeed did not affect their ability to stimulate CD4+ Th cell proliferation in response to superantigen. However, as a result of their defective production of bioactive IL-12, GC-pretreated DC have a reduced ability to promote the production of IFN-gamma in CD4+ Th lymphocytes, as shown by the observation that IFN-gamma production could be restored by exogenous IL-12. In contrast, GC treatment of DC enhanced the secretion of the antiinflammatory cytokine IL-10 and the type 2 cytokine IL-5 by the T cells. It is concluded that, in addition to their role as potent inhibitors of inflammation via the direct suppression of cytokine production in T cells, GC may further inhibit T cell-mediated inflammation indirectly via the suppression of IL-12 production by DC.